Relationships Among Circulating Levels of Hemostasis Inhibitors, Chemokines, Adhesion Molecules, and MRI Characteristics in Multiple Sclerosis

Abstract

Background: Several studies suggested cross talk among components of hemostasis, inflammation, and immunity pathways in the pathogenesis, neurodegeneration, and occurrence of cerebral microbleeds (CMBs) in multiple sclerosis (MS). Objectives: This study aimed to evaluate the combined contribution of the hemostasis inhibitor protein C (PC) and chemokine CC motif ligand 18 (CCL18) levels to brain atrophy in MS and to identify disease-relevant correlations among circulating levels of hemostasis inhibitors, chemokines, and adhesion molecules, particularly in CMB occurrence in MS. Methods: Plasma levels of hemostasis inhibitors (ADAMTS13, PC, and PAI1), CCL18, and soluble adhesion molecules (sNCAM, sICAM1, sVCAM1, and sVAP1) were evaluated by multiplex in 138 MS patients [85 relapsing-remitting (RR-MS) and 53 progressive (P-MS)] and 42 healthy individuals (HI) who underwent 3-T MRI exams. Association of protein levels with MRI outcomes was performed by regression analysis. Correlations among protein levels were assessed by partial correlation and Pearson's correlation. Results: In all patients, regression analysis showed that higher PC levels were associated with lower brain volumes, including the brain parenchyma (p = 0.002), gray matter (p < 0.001), cortex (p = 0.001), deep gray matter (p = 0.001), and thalamus (p = 0.001). These associations were detectable in RR-MS but not in P-MS patients. Higher CCL18 levels were associated with higher T2-lesion volumes in all MS patients (p = 0.03) and in the P-MS (p = 0.003). In the P-MS, higher CCL18 levels were also associated with lower volumes of the gray matter (p = 0.024), cortex (p = 0.043), deep gray matter (p = 0.029), and thalamus (p = 0.022). PC-CCL18 and CCL18-PAI1 levels were positively correlated in both MS and HI, PC-sVAP1 and PAI1-sVCAM1 only in MS, and PC-sICAM1 and PC-sNCAM only in HI. In MS patients with CMBs (n = 12), Ziliotto et al. Hemostasis, Chemokines, and Adhesion Molecules in MS CCL18-PAI1 and PAI1-sVCAM1 levels were better correlated than those in MS patients without CMBs, and a novel ADAMTS13-sVAP1 level correlation (r = 0.78, p = 0.003) was observed. Conclusions: Differences between clinical phenotype groups in association of PC and CCL18 circulating levels with MRI outcomes might be related to different aspects of neurodegeneration. Disease-related pathway dysregulation is supported by several protein level correlation differences between MS patients and HI. The integrated analysis of plasma proteins and MRI measures provide evidence for new relationships among hemostasis, inflammation, and immunity pathways, relevant for MS and for the occurrence of CMBs.

Crosstalk between hemostasis inhibitors and cholesterol biomarkers in multiple sclerosis

“…Notably, the strength of the associations of PC with BPV, GMV and NCV were not weakened when Apo-CII, ApoB and other CPB were included as a predictor. These results build on and substantially extend our earlier work 14,15,26 on hemostasis markers in MS by including the clinically relevant focus on CPB.…”

“…17 It is also noteworthy that PC antigen has negative rather than positive associations with MRI measures of brain volume. 26 ity that MS neurodegeneration can be facilitated when there is dysregulation of a key anticoagulation biomarkers such as PC. Our results do not support a role for CPB in the PC associations with MRI measures.…”

“…In our earlier report, we found that greater PC was associated with lower BPV and GMV as assessed by quantitative MRI. 26 We therefore investigated whether or not the associations of PC with BPV, GMV and NCV were abrogated by including CPB as predictors. Table 3 summarizes the regression results for PC without CPB and for PC and individual CPB when both were included as predictors.…”

Circulating Vascular Cell Adhesion Molecule-1 (sVCAM-1) Is Associated With Left Atrial Remodeling in Long-Distance Runners

“…Soluble vascular cell adhesion molecule-1 (sVCAM-1), a possible biomarker of the process of fibrosis and cardiac remodeling as a consequence of physical exercise ( 14 ), plays a key role in the adhesion of inflammatory molecules and transmigration of leukocytes to the vascular intima ( 15 ); it can cause endothelial dysfunction, thus affecting the regulation of cardiac blood flow. In this regard, aerobic exercise has been shown to increase its expression and induce cellular infiltration and inflammation of the heart tissue in untrained subjects ( 16 ) as well as patients with peripheral vascular disease ( 17 ).…”

Editorial: Update on Vascular Contributions to Age-Related Neurodegenerative Diseases and Cognitive Impairment - Research of ISNVD 2020 Meeting

“…They found decreased brain perfusion in both cortical and deep GM is associated with poorer MS outcomes, but not with the presence of CVD. By combining plasma and MRI biomarkers of MS, Ziliotto et al ( 10 ) investigated the link between microvascular abnormalities and immune inflammatory changes and their role in neurodegeneration. They showed that higher protein C (PC) levels were associated with large brain volume loss in relapsing remitting but not in progressive MS. Higher chemokine C-C motif ligand 18 (CCL18) levels were associated with higher T2-lesion volumes in all MS patients, and higher CCL18 levels were associated with lower volumes of the GM in progressive MS.…”